P1058: CHILDHOOD-ONSET ERDHEIM-CHESTER DISEASE IN THE MOLECULAR ERA: CLINICAL PHENOTYPE AND LONG-TERM OUTCOME OF 21 PATIENTS
Authors: Francesco Pegoraro, Martina Mazzariol, Irene Trambusti, Saamer Bakhshi, Saumyaranjan Mallick, Ira J. Dunkel, Van den Bos Cor, Ozlem Tezol, Shijun Shan, Suheyla Ocak, Flavio Giordano, Carmen De Fusco, Stefania Gaspari, Jean Donadieu, Eli Diamond, Jean-Francois Emile, Elena Sieni, Julien Haroche, Augusto Vaglio
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that almost exclusively affects adults. Childhood-onset ECD is anecdotal, and its clinical and molecular characterization is still inadequate; similarly, data on response to treatment and long-term sequelae are lacking. Aims: To describe the largest multicenter series reported so far of patients with childhood-onset ECD, focusing on their clinical and molecular phenotype, treatment, and outcome. Methods: Prevalent and incident cases with a biopsy-proven diagnosis of ECD or mixed ECD-Langerhans cell histiocytosis (LCH) were considered eligible if they had: a) age at ECD onset <18 years; b) clinical presentation consistent with ECD with at least one typical localization (bilateral, sclerotic long-bone involvement; peri-renal infiltration; large-vessel infiltration; pseudotumoral atrial involvement or other typical cardiac manifestations; xanthelasma-like lesions); c) available data on BRAF status; d) available data on treatment and outcome (minimum follow-up of six months). Results: Twenty-one patients were included (12 females). The median age at symptom onset and diagnosis was respectively 5 (IQR 2-8) and 6 years (IQR 3.5-11.5). The main clinical manifestations were systemic symptoms, polyuria/polydipsia, bone pain, and neurological deficits. The most frequently affected sites were the bones (n=18, 86%), the facial/orbital area (n=14, 67%), the central nervous system (CNS; n=13, 62%), and the hypothalamic-pituitary region (n=12, 57%). Other involved sites included the skin (n=9, 43%) and the peri-renal area (n=5, 24%), while peri-aortic, cardiac, or pulmonary lesions were rare (n=3 each, 14%). Eight patients (38%) had clinical and/or pathology findings consistent with mixed ECD/LCH, and they had significantly higher frequency of systemic symptoms and diabetes insipidus. Twelve patients (57%) harbored the BRAFV600E mutation and one a MAP2K1 mutation; BRAFV600E mutated patients presented more frequently with exophthalmos. First-line treatment regimens included chemotherapy (n=8, 38%), interferon-α (n=6, 29%), and targeted approaches (BRAF, MEK, or mTOR inhibitors; n=6, 29%). Ten patients (48%) required more than one line of treatment due to toxicity or disease progression. Best objective responses were reported in patients receiving BRAF or MEK inhibitors (complete or partial responses in all treated patients) and interferon-α (partial response in 5/8 patients). The median follow-up was 49 months (IQR 25-84). At last follow-up, two patients died (one for chemotherapy-related toxicity and the other for unknown causes), and the remaining 19 had either stable disease (n=2) or response (n=17). Ten patients (48%) had treatment-related side effects, which required treatment discontinuation in eight cases. Most patients also experienced long-term sequelae (mostly involving the endocrine and the osteoarticular system); in some cases, renal, ocular, and neuropsychiatric events were reported as well. Summary/Conclusion: Pediatric ECD is a rare and challenging condition. Its phenotype is similar to that of adult ECD; however, localizations such as the facial/orbital area, the CNS, and the hypothalamic/pituitary region are more common in children, as it is for mixed ECD/LCH. Targeted treatments used for adult ECD, such as BRAF and MEK inhibitors, seem effective in the pediatric population as well, but a tailored therapeutic and follow-up strategy is always required, considering the long-term concerns in this age group.Keywords: Molecular, Myeloid